Central neurodegeneration in Kennedy's disease accompanies peripheral motor dysfunction

Abstract

Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R² = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R² = 0.59, p < 0.01), motor (R² = 0.63, p < 0.01), and somatosensory (R² = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.

Keywords: Amyotrophic lateral sclerosis; Diffusion-weighted imaging; Kennedy’s disease; MRI; Peripheral nerve; Spinobulbar muscular atrophy.

Figure 1

Diffusivity of corticospinal tracts were assessed between cortical grey/white matter boundary to the level of the inferior boundary of the lateral ventricles, at which point corticospinal tracts demonstrated marked intra-voxel overlap. Axonal degeneration was observed within juxtacortical white-matter of corticospinal tracts (premotor; motor; somatosensory) in ALS and SBMA patients, relative to healthy control participants. Representative 3D reconstruction of delineated tracts from a healthy control participant is shown in native space. SBMA patients demonstrated widespread increase in axial diffusivity across all reconstructed corticospinal tracts across left and right hemispheres. ALS patients demonstrated a selective increase in axial diffusivity specific to corticospinal streamlines seeded from the primary motor and somatosensory cortices. Mean and standard deviation. *Indicates significance at p < 0.05; **indicates significance at p < 0.01; Bonferroni corrected.

Figure 2

Increased white matter abnormality along corticospinal tracts (premotor; motor; somatosensory) in SBMA patients was significantly correlated with total neuropathy score clinical version (TNSc).